In order to perform a laparoscopy the abdomen, which is a virtual cavity, has to be insufflated in order to create a working space. Insufflation pressure is limited to 15 mm of Hg out of fear of gas embolism, although this limit has not been substantiated clinically. CO2 has been traditionally used as a gas for the pneumoperitoneum out of safety concerns. Indeed CO2 has a high solubility in water and an high exchange capacity in the lungs. Therefore the risk of a gas embolism causing a hearth tamponnade should be minimal.
During laparoscopic surgery some flow through the abdominal cavity is necessary in order to evacuate smoke generated by the use of electro-surgery or of a CO2 laser. Especially the high flows used together with a CO2 laser, can induce important uncontrolled desiccation and temperature alterations in the abdominal cavity.
During open surgery, the abdominal content is directly exposed to the air with important desiccation and exposure of the superficial cells to 20% of oxygen, proven to be toxic for the mesothelial cell layer. In addition, during open surgery manipulation of bowels is more important than during laparoscopy. During open surgery the abdominal cavity is exposed to the ambient temperature.
During surgery, both laparoscopy and laparotomy, the mesothelial cells and the peritoneal cavity thus are exposed to a series of traumas such as mechanical trauma, cellular hypoxia (ie a partial pressure of oxygen less than 7 mm Hg or less than 1% of oxygen at atmospheric pressure) or hyperoxia, (i.e. a partial pressure of oxygen more than 70 mm Hg or more than 10% of oxygen at atmospheric pressure) and desiccation. The effects of these trauma's upon the mesothelial cells are additive Simultaneously surgery can be associated with important temperature changes of the cells, a decrease of temperature being rather beneficial by making cells more resistant to trauma. It is to be noticed that surgical interventions in the human occasionally may be very long interventions.
Adhesions following surgery are clinically important and cause suffering to the patients and a burden for the cost of health care. Adhesions form in the majority of men and women after surgery both after laparotomy and after laparoscopy. For example, following abdominal surgery both by laparotomy and by laparoscopy, adhesions form in over 70% of women. The clinical impact can best be illustrated as follows. Postoperative adhesions are estimated to be responsible for 30% of all chronic abdominal pain, for 30% of all infertility and for over 90% of all bowel obstructions. After abdominal surgery the incidence of reoperation and of bowel obstruction keeps rising almost linearly for at least 10 years. Re-interventions occur in some 30%, in many persons more than once, and at least 6% are linked directly to adhesion formation. Repeat surgery moreover is more difficult, more tedious and associated with more complications because of adhesions. From these findings, models have been constructed indicating an enormous cost of adhesions formation for society besides the cost of suffering of the individuals.
Adhesion formation between opposing injured peritoneal surfaces are acknowledged to be different from adhesion reformation following lysis of adhesions and from de novo adhesion formation outside the areas of surgery. Only prevention of adhesion formation has been investigated adequately. Clinical adhesion prevention in the human until today has been based upon the classic model of adhesion formation, i.e. describing adhesion as a local process between two opposing lesions.
Good surgical practice and gentle tissue handling were suggested as important by the pioneers of microsurgery. This comprised, moistening of tissues by continuous irrigation and minimal mechanical trauma.
Besides good surgical practice, adhesion prevention in the human has been limited to barriers and flotation agents with a reduction of adhesion formation that ranges for all products between 40% to 50%. It is important to note that for none of these products efficacy has been proven for endpoints that really matter, i.e. pain, infertility, bowel obstruction or reoperation rate. This can be explained by the high intra-individual variability, and the variability in surgical interventions which make adequate randomized clinical trials prohibitively large.
Sheet barriers such as Seprafilm (Hyaluronic acid-carboxymethylcellulose), Interceed (Oxidized regenerated cellulose) and Gore-tex(Expanded polytetrafluoroethylene) are proven effective but did not become very popular for various reasons. Seprafilm is difficult to use during laparoscopy whereas to be efficacious any remaining bleeding of the traumatized area should be avoided.
Since Intergel (0.5% ferric hyaluronate gel) has been withdrawn from the market, only Hyalobarrier gel(Auto-cross linked hyaluronic acid gel), Spraygel (Polyethylenglycol) and Intercoat/Oxiplex remain available for clinical use. Overall efficacy appears to be similar for all 3 products. A comparison between these 3 gels can unfortunately not be made since comparative trials do not exist.
Whereas in the human the efficacy of Ringers lactate as a flotation agent has not been proven, Adept, (Icodextrin) a macromolecular sugar with a higher retention time in the peritoneal cavity, was expected and shown to be efficacious in adhesion reduction. A major advantage is the safety and absence of side effects, which were well established since extensively used for peritoneal dialysis. The strength of the available evidence demonstrating efficacy, is in a Cochrane review not considered very solid.
It is beyond the scope of this application to discuss in detail the specificities of the animal models. The most comprehensive model today is the laparoscopic mouse model since most of the available products and the role of the peritoneal cavity have been investigated in detail. In this model it was demonstrated that gentle tissue handling and the conditioning of the pneumoperitoneum were the first and quantitatively the most important steps in adhesion prevention. It was demonstrated that adhesions could be decreased by humidification, by preventing mesothelial hypoxia by adding some 4% of oxygen to the CO2 pneumoperitoneum, and by cooling slightly the peritoneal cavity. In this model, dexamethasone further decreased adhesions, whereas anti-inflammatory agents (NSAID's, COX1, COX2 inhibitors) and anti-TNFa monoclonals were close to ineffective.
In the mouse laparoscopic model it was equally demonstrated that adding more than 10% of oxygen to the CO2 pneumoperitoneum increased adhesion formation, probably through the formation of ROS, an increase that could be diminished by decreasing the partial oxygen pressure to the normal physiologic partial pressure in peripheral cells ie between 20 and 40 mm of Hg partial oxygen (pO2) pressure.
The addition of oxygen to the pneumoperitoneum for reduction of adhesion formation has been described in WO98/50064. It has been demonstrated with CO2 as carrier gas. He and N2O were suggested as alternative carrier gasses.
Prevention of angiogenesis, a consequence of hypoxia also reduces adhesion formation, as demonstrated in PIGF knockout mice and by the administration of anti VEGF and anti PIGF monoclonal antibodies.
By way of illustration, FIG. 1 indicates the effect of prevention of adhesion formation in a laparoscopic mouse model as known in 2008. Minimizing mesothelial damage by preventing desiccation, gentle tissue handling, adding oxygen and cooling decrease adhesion formation by some 75%. Adhesions can decrease further by adding Reactive Oxygen Scavengers (ROS), calcium channel blockers, phospholipids or dexamethasone. In addition Barrier gels, as used in the human, can be used achieving over 90% adhesion reduction. If in this model calcium channel blockers, phospholipids, anti-angiogenic monoclonals and fibroblast manipulation would have additional effects possibly reducing adhesion reduction by close to 100%.